Cystic fibrosis is a hereditary life-threatening disorder that causes severe lung damage and nutritional deficiencies. Cystic fibrosis (“CF”) is caused by defects in the cystic fibrosis transmembrane conductance regulator (CFTR) protein, which results from mutations in the CFTR gene. CFTR protein channels regulate chloride ion and water flow in and out of a cell. The transport of salt ions and water keeps the lungs and other organs hydrated. In people with certain CFTR gene mutations, the CFTR protein channels do not function properly, resulting in an imbalance of salt and water. This leads to the buildup of abnormally thick and sticky mucus in the lungs and other organs, which often become infected.
CFTR is activated by cAMP elevation and PKA activation, via PDE3 or PDE4 inhibition. Thus, a cAMP elevating agent, such as a PDE4 inhibitor, would be useful in the treatment of CF by activating CFTR. Roflumilast is an example of a PDE4 inhibitor which has shown activating effects on CFTR. See Liu, S. et al., J. Pharmacol Exp Ther., 2005, 314(2): 846-54.
Ivacaftor (KALYDECO™ or VX-770) is a CFTR potentiator indicated for the treatment of CF in patients having a G551D mutation in the CFTR gene. See WO 2011/050325 A1. A very small percentage of the CF patient population has the G551D mutation, approximately 4% or 1200 patients in the United States. Another mutation in the CF gene which occurs in approximately 3% of CF patients in the United States is the R1 17H mutation. Ivacaftor is not approved for CF patients having more common mutations in the CFTR gene, such as the delF508 mutation. The delF508 mutation impairs the folding, stability and gating of CFTR protein. CFTR corrector compounds, such as lumacaftor (VX-809) or Corr-4a, can partially alleviate the folding defect. Still, there is an unmet need to find an effective treatment of CF, including in patients having CFTR mutations other than the G551D mutation.